Atomoxetine (Page 9 of 11)

Mutagenesis

Atomoxetine hydrochloride was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration).

The metabolite N-desmethylatomoxetine hydrochloride was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test.

Impairment of fertility

Atomoxetine hydrochloride did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

14.1 ADHD Studies in Children and Adolescents

Acute Studies

The effectiveness of atomoxetine hydrochloride in the treatment of ADHD was established in 4 randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes.

Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for atomoxetine hydrochloride- and placebo-treated patients using an intent-to-treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV.

In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of atomoxetine hydrochloride (0.5, 1.2, or 1.8 mg/kg/day) or placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses, improvements in ADHD symptoms were statistically significantly superior in atomoxetine hydrochloride-treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day atomoxetine hydrochloride dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day atomoxetine hydrochloride dose was not superior to placebo.

In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either atomoxetine hydrochloride or placebo. Atomoxetine hydrochloride was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of atomoxetine hydrochloride was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on atomoxetine hydrochloride compared with placebo, as measured on the ADHDRS scale. This study shows that atomoxetine hydrochloride is effective when administered once daily in the morning.

In 2 identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children aged 7 to 13 (Study 3, N=147; Study 4, N=144), atomoxetine hydrochloride and methylphenidate were compared with placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended atomoxetine hydrochloride dose was 2 mg/kg/day. The mean final dose of atomoxetine hydrochloride for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on atomoxetine hydrochloride than on placebo, as measured on the ADHDRS scale.

Examination of population subsets based on gender and age (<12 and 12 to 17) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups.

Maintenance Study

The effectiveness of atomoxetine hydrochloride in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6 to 15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about 4 weeks during an initial 10 week open-label treatment phase with atomoxetine (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of atomoxetine (N=292) or to placebo (N=124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score ≤ 2 and a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to atomoxetine and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of atomoxetine (N=81) or to placebo (N=82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥ 90% of study entry score for 2 consecutive visits. In both double-blind phases, patients receiving continued atomoxetine treatment experienced significantly longer times to relapse than those receiving placebo.

14.2 ADHD Studies in Adults

The effectiveness of atomoxetine hydrochloride in the treatment of ADHD was established in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older, who met DSM-IV criteria for ADHD.

Signs and symptoms of ADHD were evaluated using the investigator-administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis.

In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either atomoxetine hydrochloride or placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of atomoxetine hydrochloride for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on atomoxetine hydrochloride, as measured on the ADHD Symptom score from the CAARS scale.

Examination of population subsets based on gender and age (<42 and ≥42) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Atomoxetine capsules USP, 40 mg* are white to off-white powder filled in size ‘1’ hard gelatin capsules with opaque dark blue colored cap and opaque dark blue colored body imprinted “RDY” on cap and “521” on body with black ink. They are supplied in bottles of 30’s, 500’s and unit dose packages of 100 (10 x 10).

Carton of 30 capsules (10 capsules each blister pack x 3), NDC 0904-6908-04

*Atomoxetine base equivalent.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

General Information

Physicians should instruct their patients to read the Medication Guide before starting therapy with atomoxetine hydrochloride and to reread it each time the prescription is renewed. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with atomoxetine hydrochloride and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking atomoxetine hydrochloride.

Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, depression, and suicidal ideation, especially early during atomoxetine hydrochloride treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Severe Liver Injury

Patients initiating atomoxetine hydrochloride should be cautioned that severe liver injury may develop. Patients should be instructed to contact their physician immediately should they develop pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms. [See Warnings and Precautions (5.2)].

Aggression or Hostility

Patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility.

Priapism

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with atomoxetine hydrochloride. The parents or guardians of pediatric patients taking atomoxetine hydrochloride and adult patients taking atomoxetine hydrochloride should be instructed that priapism requires prompt medical attention.

Ocular Irritant

Atomoxetine hydrochloride is an ocular irritant. Atomoxetine capsules are not intended to be opened. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Drug-Drug Interaction

Patients should be instructed to consult a physician if they are taking or plan to take any prescription or over-the-counter medicines, dietary supplements, or herbal remedies.

Pregnancy Registry

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to atomoxetine during pregnancy [see Use in Specific Populations (8.1)].

Food

Patients may take atomoxetine capsules with or without food.

Missed Dose

If patients miss a dose, they should be instructed to take it as soon as possible, but should not take more than the prescribed total daily amount of atomoxetine hydrochloride in any 24-hour period.

Interference with Psychomotor Performance

Patients should be instructed to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.

Rx Only

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Made in India

Distributed By:

MAJOR® PHARMACEUTICALS

Livonia, MI 48152

Revised: 0320

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